Epibatidine (exo-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane) is isolated in minute amounts from an Ecuadoran poison frog Epipedobates tricolor. Its structure and limited biological properties were first reported in 1992 [see J. Am. Chem. Soc., 114, 3475 (1992)]. It is described as a non-opioid analgesic with about 200-500 times the analgesic properties of morphine. It is clear that epibatidine and/or analogs have tremendous pharmaceutical potential for the treatment of pain. The structure of epibatidine is shown as formula I, below: ##STR1##
In 1993, four syntheses of epibatidine were reported, including two that are enantioselective [J. Chem. Soc., Chem. Commun., 1216 (1993); Tetrahedron Lett, 34, 4477 (1993); Tetrahedron Lett., 34, 3251 (1993); J. Am. Chem. Soc., 58, 5600 (1993)]. All of these syntheses are rather lengthy, requiring 4-17 steps, and all involve as a key step the cyclization of a cyclohexane-containing amine. It is clear that these relatively inefficient syntheses are not practical for the industrial preparation of epibatidine and analogs. Therefore, a need exists for new syntheses of epibatidine and analogs thereof, which are shorter and/or proceed in higher yield.